TABLE 3. Open-label investigations in patients described as refractory to other treatments[10]

Specific etiology

PTSD is relatively unique among psychiatric disorders in requiring a specific etiology. Treatment must first address the specific individualized aspects of the trauma itself and contextualize its role in the patient’s life. Certain types of trauma can reduce the likelihood of spontaneous recovery (eg, PTSD due to medical illness2) or response to treatment: childhood abuse-related trauma, repeated or prolonged trauma, more severe trauma, and trauma associated with marked impairment of self-regulation. Combat PTSD is frequently regarded as less responsive to standard treatments than single-event civilian trauma-associated PTSD.

Comorbid substance use, severe anger dyscontrol, mood disorders, or personality disorders understandably make treatment more difficult and complex. The evidence is mixed on whether compensation seeking per se reduces the likelihood of benefit from treatment. Finally, some traumatic experiences such as disaster or terrorism (which may include losses of significant others, physical injuries, occupational and other practical alterations, or cultural dislocation) usually require interpersonal support and practical interventions.

Different components of the clinical syndrome may respond differently to different interventions. When medications are effective, they usually provide more benefit for intrusive and hyperarousal, than avoidance symptoms. Exposure therapy directly addresses avoidance, which is also improved with other forms of TF-CBT (as are intrusive and hyperarousal symptoms). To date, few trials have utilized DSM-5 criteria, which include additional symptoms (negative alterations in cognitions and emotions) to those in DSM-IV. A recent meta-analysis of 93 RCTs found that treatments effective for PTSD are also effective for improving comorbid depressive symptoms (which overlap to some extent with DSM-5 PTSD Cluster D symptoms).14

Some PTSD subtypes may require specific treatments. PTSD with psychotic features, while not included in DSM-IV or DSM-5, is well recognized and is a better indication for atypical antipsychotic augmentation of antidepressants than PTSD per se.5,15 Complex PTSD, which includes prominent difficulties in self-regulation capacity, may respond to focused CBT but often requires a “staged” approach.

Conclusion

There is no “best” evidence-based treatment for all patients, and this is true for treatment-resistant PTSD. Pharmacologic management must be individualized, and the use of focused CBT in conjunction with pharmacotherapy may require careful, flexible integration, sometimes across months or years of treatment—as in Ms. A’s and Mr. B’s cases. Still, as also illustrated by Mr. B’s case, empirical data summarized in Tables 2 and 3 may be of value in making medication changes.

There are medications with expert recommendations against their use (benzodiazepines), with uniformly negative RCTs (divalproex, bupropion, guanfacine, tiagabine), or with a mixture of both positive and negative evidence (fluoxetine, mirtaza­pine, risperidone and olanzapine augmentation of antidepressants, topiramate). Furthermore, some commonly used pharmacologic agents have not been subject to RCTs in PTSD (citalopram, escitalopram, gabapentin, clonidine, lithium), nor have many newer agents such as levomilnacipran, milnacipran, vilazodone, vortioxetine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Given the challenges in helping people with treatment-resistant PTSD, it was not surprising to find an impressive variety of alternative pharmacologic agents that have shown benefit in at least some treatment-resistant patients (Table 3). Future research may lead to agents that directly address neuropharmacologic mechanisms of extinction in the amygdala including glutamate/NMDA modulators.16 At this time, evidence on the risk-to-benefit ratio for marijuana/cannabinoids does not justify a recommendation for treatment-resistant PTSD.17

While RCTs of medications typically involve weekly to bimonthly follow-up visits, and prolonged exposure therapy and cognitive-processing therapy require weekly visits for standard implementation, for many patients, such frequency of visits is limited by practical considerations (eg, cost, work obligations). This was true for Ms. A and Mr. B. For many patients like Ms. A and Mr. B, who have suffered for years, it may not be surprising to find that medication changes may take months or longer to achieve optimal benefit, and some components of focused CBT involve changes in maladaptive habits, ingrained after trauma, that take time to implement.